Radiation necrosis is a severe, but late occurring, type of injury to normal tissue that can lead to significant challenges in the management of brain-tumor patients following radiation therapy. Radiation necrosis causes focal neurological sequelae that limit patients' quality of life. Quantitative methods to identify and stage radiation necrosis are of paramount importance in the neuro-oncology community. Additionally, the identification of neuroprotectants that could reduce the incidence or severity of radiation necrosis and therapeutics that could mitigate symptoms would have significant positive impact on patient care. The need for non-invasive, quantitative characterization methods is a particular challenge for diagnosing tissue radiation- damage in the brain. This proposal offers an important advance to meet this critical need. Magnetic resonance imaging (MRI) can provide non-invasive characterization, through measurement of parameters that are sensitive to important physiologic and cellular parameters, including cell density, cerebral blood volume and flow, oxygen utilization, and vascular permeability or leakiness. A detailed understanding of the factors that affect the onset and progression of radiation necrosis requires the development of robust animal models that enable a clear histologic (cellular) description of tissue damage in the irradiated brain. The goals of this application are to develop a well-characterized mouse model of radiation necrosis, to validate non-invasive, translatable MRI tools for identifying necrosis in this model, and subsequently to investigate mechanisms by which this tissue damage can be prevented or mitigated through therapeutic interventions. More specifically, the aims of the grant to: 1) optimize a recently developed mouse model of radiation necrosis in brain; 2) develop and validate MRI markers that can uniquely identify radiation necrosis; 3) test putative neuroprotectant or therapeutic compounds and monitor their efficacy in reducing radiation damage by non-invasive MR imaging techniques. The project will make use of a number of cutting-edge experimental techniques including high field strength small-animal MRI equipment and advanced imaging sequences. Mice will be irradiated using the Leksell Gamma Knife Perfexion unit, a state-of-the-art unit used for stereotactic irradiation of patients with benign and malignant brain tumors, and following the establishment of radiation necrosis, novel interventional mechanisms will be tested for the prevention and mitigation of tissue damage. This series of experiments will result in a significantly clearer understanding of the brain tissue changes that follow cranial irradiation. The ability to monitor these changes non-invasively, and to prevent and mitigate these changes with therapeutic interventions, will lead to better clinical outcomes and improved quality of life for patients with brain tumors whose treatment paradigms include radiation therapy.